Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
  • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings

Definitions

• the present invention relates to an ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative which is a novel useful compound as an intermediate for the synthesis of pharmaceuticals.
• This ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative is a useful compound as an intermediate commonly used for the synthesis of various HMG-CoA (3-hydroxyglutaryl coenzyme A) reductase inhibitors whose action as an anti-hyperlipemia has attracted attentions.
• the below-described compound (a) is oily matter, from which a crude product (b) is obtained as oily matter by isolating and purifying the oily matter (a) by chromatography on a silica gel column, followed by reductive debenzylation. Chromatography on a silica gel column, however, is not suited for production on an industrial scale.
• Bn means a benzyl group and t Bu means a tert-butyl group.
• tert-butyl (3R,5S)-3,5-O-isopropylidene-3,5,6-trihydroxyhexanoate (b) having the 6-hydroxyl group deprotected is a particularly important compound, because the 6-position of the (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative is a bonding site to another compound.
• Bz represents a benzoyl group
• t Bu means a tert-butyl group
• Ac means an acetyl group
• X represents a chlorine atom, a bromine atom or a nitro group.
• An object of the present invention is therefore to prepare, safely in a high yield in a simple manner, a (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative which can satisfy the above-described demands, is in the form of crystals permitting easy handling and has high chemical purity.
• the present invention therefore embraces the following aspects.
• R 1 represents a benzyl group which may have a substituent, a triphenylmethyl group which may have a substituent, an organosilyl group or a C 1-5 acyl group; and A represents at least one amine selected from the group consisting of a primary amine represented by the following formula (IIIa):
• R 4 and R 5 are the same or different and each independently represents a C 5-7 alicyclic group
• cinchamidine cinchotine
• cinchonamine cinchonidine
• cinchonine cinchonine
• R 1 has the same meaning as described above.
• a process for producing a high-purity ammonium (3R,5S)-3,5,6-trihydroxyhexanoate in the form of crystals which comprises causing the amine (A) as described above in 1) to act on the (3R,5S)-3,5,6-trihydroxyhexanoic acid represented by the formula (II) and crystallizing the resulting ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative precursor to improve the chemical purity thereof.
• R 1 represents a benzyl group which may have a substituent, a triphenylmethyl group which may have a substituent, an organosilyl group or a C 1-5 acyl group.
• R 1 include a benzyl group which may have a substituent, for example, a lower C 1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, a lower C 1-4 alkoxy group such as methoxy, ethoxy, propoxy or butoxy, or a halogen atom such as fluorine, chlorine, bromine or iodine; a triphenylmethyl group which may have a substituent, for example, a lower C 1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, a lower C 1-4 alkoxy group such as methoxy, ethoxy, propoxy or butoxy, or a halogen atom such as fluorine, chlorine, bromine or
• R 1 examples include benzyl, triphenylmethyl, tert-butyldimethylsilyl and acetyl groups.
• A represents an amine
• the amine (A) is at least one amine selected from the amines represented by the above-described formulas (IIIa), (IIIb) and (IIIc), cinchamidine, cinchotine, cinchonamine, cinchonidine and cinchonine.
• R 2 in the formula (IIIa) include C 1-7 alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, pentyl, hexyl and heptyl; and C 5-7 alicyclic groups such as cyclopentyl, cyclohexyl and cycloheptyl.
• Ar in the formula (IIIb) include phenyl groups which may have a substituent such as phenyl, p-tolyl and xylyl.
• R 4 or R 5 in the formula (IIIc) include C 5-7 alicyclic groups such as cyclopentyl, cyclohexyl and cycloheptyl.
• amine (A) are as follows: primary amines of the formula (IIIa), for example, alkyl-containing primary amines such as propylamine and tert-butylamine, and alicyclic primary amines such as cyclohexylamine; primary amines of the formula (IIIb), for example, benzyl-containing primary amines such as benzylamine, phenylethylamine and phenylethanolamine; secondary amines of the formula (IIIc), for example, alicyclic secondary amines such as dicyclohexylamine; cinchonidine; and cinchonine. More preferred are primary amines such as propylamine, tert-butylamine, cyclohexylamine, benzylamine, phenylethylamine and phenylethanolamine.
• primary amines of the formula (IIIa) for example, alkyl-containing primary amines such as propylamine and tert-buty
• ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative of the invention is prepared in accordance with the following reaction.
• R 1 represents a benzyl group which may have a substituent, a triphenylmethyl group which may have a substituent, an organosilyl group or a C 1-5 acyl group and A means an amine.
• the ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative (I) is prepared in the form of crystals by causing the above-described amine (A) to act on (3R,5S)-3,5,6-trihydroxyhexanoic acid (II) as a starting material and then, cooling the reaction product.
• the (3R,5S)-3,5,6-trihydroxyhexanoic acid (II) to be used in the invention is available by a known manner, for example, that described in JP-A-2-289537 or JP-A-6-65226.
• the amine (A) is used in an amount of 1 to 2 times, more preferably 1 to 1.3 times the mole relative to 1 mole of the (3R,5S)-3,5,6-trihydroxyhexanoic acid (II).
• reaction solvent usable are those which do not adversely affect the reaction.
• examples include esters such as methyl acetate, ethyl acetate, propyl acetate and butyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane and 1,3-dioxolan; ketones such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone and cyclohexanone; alcohols such as methanol, ethanol, isopropyl alcohol and butanol; acetonitrile; and water; and mixed solvents thereof.
• the above-exemplified solvent is usually employed in an amount of 1 to 100 times the volume, preferably 1 to 50 times the volume, of the mass (or volume) of the (3R,5S)-3,5,6-trihydroxyhexanoic acid (II).
• This reaction is usually conducted in an inert gas atmosphere such as nitrogen gas or argon gas. This reaction is usually conducted for about 30 minutes to 10 hours at a temperature of about 20 to 50° C. By subsequent stirring at about ⁇ 20 to 50° C. for 1 to 10 hours, reaction is terminated, whereby an ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative (I) can be obtained as crystals.
• an ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative (I) can be obtained as crystals.
• the above-described conditions can be changed as needed, depending on the kind of the amine (A) to be employed.
• the ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative (I) of the present invention thus prepared is in the form of crystals as is apparent from Examples which will be described later. Crystallization makes it possible to prepare the derivative at a high selectivity to the syn-isomer [(3R,5S)-isomer] relative to the anti-isomer and even if the preparation ratio of the syn-isomer is insufficient, high-purity syn-isomer [(3R,5S)-isomer] is available by recrystallization.
• a ratio of the syn-isomer to the anti-isomer ranging from 99.0/1.0 to 100/0, preferably 99.1/0.9 to 100/0, more preferably 99.4/0.6 to 100/0 can be attained.
• the derivative of the present invention is obtained in the form of crystals, it has stability by far superior to that in the oily form.
• the invention which facilitates the purification by preparing its ammonium salt derivative (I) in the form of crystals, brings about a large merit in the synthesis research of an HMG-CoA reductase inhibitor.
• TMS tetramethylsilane
• DSS sodium 2,2-dimethyl-2-silapentane-5-sulfonate
• Injection temperature 200° C.
• a 100 ml egg-plant type flask was charged with 2.80 g (6.08 mmol) of methyl (3R,5S)-6-triphenylmethyloxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate (4a) and 30 ml of ethanol.
• the resulting mixture was cooled to 10° C.
• 2.43 g (6.08 mmol) of a 10% aqueous solution of sodium hydroxide 50 ml of water was charged further.
• the resulting mixture was stirred overnight at room temperature and then stirred at 35° C. After concentration, the residue was added with a 5% aqueous hydrochloric acid solution until the pH became 3, followed by extraction with toluene.
• a 100 ml egg-plant type flask was charged with 7.6 g (19.4 mmol) of benzyl (3R,5S)-6-tert-butyldimethylsilyloxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate (6) and 10 ml of THF. After cooling to 10° C., 34.0 ml of a 1M THF solution of tetrabutylammonium fluoride (TBAF) was added dropwise to the reaction mixture. The temperature was allowed to rise back to room temperature, at which stirring was conducted for 2 hours. To the reaction mixture was added 40 ml of a saturated solution of ammonium chloride to separate an oil layer.
• TBAF tetrabutylammonium fluoride
• a 100 ml egg-plant type flask was charged with 5.8 g (19.7 mmol) of benzyl (3R,5S)-3,5-O-isopropylidene-3,5,6-trihydroxyhexanoate (7) and 30 ml of pyridine. After cooling to 10° C., 3.6 g (34.9 mmol) of acetic anhydride was added dropwise. After completion of the dropwise addition, the temperature was allowed to rise back to room temperature, at which stirring was conducted for 6 hours. Water (10 ml) and 20 ml of toluene were charged and the mixture was stirred. The oil layer was then separated from the reaction mixture. The water layer was extracted with 20 ml of butyl acetate.
• Injection temperature 200° C.
• Injection temperature 200° C.
• Injection temperature 200° C.
• Injection temperature 200° C.
• Injection temperature 200° C.
• Injection temperature 200° C.
• Injection temperature 200° C.
• Injection temperature 200° C.
• Injection temperature 200° C.
• Injection temperature 200° C.
• Injection temperature 200° C.
• ammonium (3R,5S)-6-benzyloxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate (101 to 10u) had a melting point of ⁇ 30° C. or less and was not handled as crystals.
• alkyl or aralkyl-containing primary amine As described above, use of an alkyl or aralkyl-containing primary amine, alicyclic primary amine or alicyclic primary amine is useful for completion of the present reaction in the invention.
• Injection temperature 200° C.
• Injection temperature 200° C.
• Injection temperature 200° C.
• Injection temperature 200° C.
• Injection temperature 200° C.
• Injection temperature 200° C.
• alkyl or aralkyl-containing primary amine, alicyclic primary amine or alicyclic secondary amine is very useful for completion of the present reaction.
• the ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative which is useful as an intermediate for the synthesis of an HMG-CoA reductase inhibitor, is stable and improved much in chemical selectivity and chemical purity. By crystallization, the derivative can be conveniently and efficiently obtained with high selectivity to its syn-isomer.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Saccharide Compounds (AREA)

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• 2000
  • 2000-08-23 JP JP2000252907A patent/JP3844112B2/ja not_active Expired - Fee Related
• 2001
  • 2001-05-18 CA CA002348166A patent/CA2348166A1/en not_active Abandoned
  • 2001-08-16 US US09/930,263 patent/US6365755B1/en not_active Expired - Lifetime
  • 2001-08-20 AT AT01402197T patent/ATE260271T1/de not_active IP Right Cessation
  • 2001-08-20 EP EP01402197A patent/EP1184380B1/de not_active Expired - Lifetime
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